Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.
Johns Hopkins Drug Discovery Program.
AIDS. 2019 May 1;33(6):973-984. doi: 10.1097/QAD.0000000000002150.
Almost half of HIV-positive people on antiretroviral therapy have demonstrable mild neurocognitive impairment (HIV-NCI), even when virologically suppressed. Intranasal insulin therapy improves cognition in Alzheimer's disease and diabetes. Here we tested intranasal insulin therapy in a model of HIV-NCI in EcoHIV-infected conventional mice.
Insulin pharmacokinetics following intranasal administration to mice was determined by ELISA. Mice were inoculated with EcoHIV to cause NCI; 23 days or 3 months after infection they were treated daily for 9 days with intranasal insulin (2.4 IU/mouse) and examined for NCI in behavioral tests and HIV burdens by quantitative PCR. Some animals were tested for hippocampal neuronal integrity by immunostaining and expression of neuronal function-related genes by real time-quantitative PCR. The effect of insulin treatment discontinuation on cognition and neuropathology was also examined.
Intranasal insulin administration to mice resulted in μIU/ml levels of insulin in cerebrospinal fluid with a half-life of about 2 h, resembling pharmacokinetic parameters of patients receiving 40 IU. Intranasal insulin treatment starting 23 days or 3 months after infection completely reversed NCI in mice. Murine NCI correlated with reductions in hippocampal dendritic arbors and downregulation of neuronal function genes; intranasal insulin reversed these changes coincident with restoration of cognitive acuity, but they returned within 24 h of treatment cessation. Intranasal insulin treatment reduced brain HIV DNA when started 23 but not 90 days after infection.
Our preclinical studies support the use of intranasal insulin administration for treatment of HIV-NCI and suggest that some dendritic injury in this condition is reversible.
即使在病毒学上得到抑制，仍有近一半接受抗逆转录病毒治疗的艾滋病毒感染者表现出明显的轻度神经认知障碍（HIV-NCI）。鼻内胰岛素治疗可改善阿尔茨海默病和糖尿病患者的认知能力。在此，我们在 EcoHIV 感染的常规小鼠的 HIV-NCI 模型中测试了鼻内胰岛素治疗。
通过 ELISA 测定鼻内给予小鼠后胰岛素的药代动力学。将 EcoHIV 接种于小鼠以引起 NCI；感染后 23 天或 3 个月，每天用鼻内胰岛素（2.4 IU/只）治疗 9 天，并通过行为测试和定量 PCR 检测 HIV 负荷来检查 NCI。一些动物通过免疫染色和实时定量 PCR 检测神经元功能相关基因的表达来测试海马神经元完整性。还检查了胰岛素治疗停止对认知和神经病理学的影响。
鼻内给予小鼠胰岛素后，脑脊液中胰岛素水平达到 μIU/ml，半衰期约为 2 小时，类似于接受 40 IU 胰岛素的患者的药代动力学参数。感染后 23 天或 3 个月开始鼻内胰岛素治疗可完全逆转小鼠的 NCI。小鼠 NCI 与海马树突棘的减少和神经元功能基因的下调相关；鼻内胰岛素逆转了这些变化，同时恢复了认知敏锐度，但在治疗停止后 24 小时内又恢复了。感染后 23 天开始鼻内胰岛素治疗可降低脑内 HIV DNA，但感染 90 天后则不可。
我们的临床前研究支持使用鼻内胰岛素治疗治疗 HIV-NCI，并表明该条件下的一些树突损伤是可逆的。
